title: (-)-Gossypol suppresses the growth of human prostate cancer xenografts via modulating VEGF signaling-mediated angiogenesis.
abstract: (-)-Gossypol, a natural BH3-mimetic and small-molecule Bcl-2 inhibitor, shows promise in ongoing phase II clinical trials for human cancers. However, whether (-)-gossypol plays functional roles in tumor angiogenesis has not been directly elucidated yet. In this study, we showed that (-)-gossypol dose dependently inhibited the expression of VEGF, Bcl-2, and Bcl-xL in human prostate cancer cells (PC-3 and DU 145) and primary cultured human umbilical vascular endothelial cells (HUVEC) in vitro. Notably, the growth of human prostate tumor PC-3 xenografts in mice was significantly suppressed by (-)-gossypol at a dosage of 15 mg/kg/d. This inhibitory action of (-)-gossypol in vivo was largely dependent on suppression of angiogenesis in the solid tumors, where VEGF expression and microvessel density were remarkably decreased. Furthermore, (-)-gossypol inhibited VEGF-induced chemotactic motility and tubulogenesis in HUVECs and human microvascular endothelial cells and suppressed microvessel sprouting from rat aortic rings ex vivo. When examined for the mechanism, we found that (-)-gossypol blocked the activation of VEGF receptor 2 kinase with the half maximal inhibitory concentration of 2.38 μmol/L in endothelial cells. Consequently, the phosphorylation of key intracellular proangiogenic kinases induced by VEGF was all suppressed by the treatment, such as Src family kinase, focal adhesion kinase, extracellular signal-related kinase, and AKT kinase. Taken together, the present study shows that (-)-gossypol potently inhibits human prostate tumor growth through modulating VEGF signaling pathway, which further validates its great potential in clinical practice.
authors.affiliation: Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Pang
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Wu
authors.forename: Yougen
authors.initials: Y
authors.lastname: Wu
authors.forename: Binbin
authors.initials: B
authors.lastname: Lu
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Jieqiong
authors.initials: J
authors.lastname: Wang
authors.forename: Zhengfang
authors.initials: Z
authors.lastname: Yi
authors.forename: Weijing
authors.initials: W
authors.lastname: Qu
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D042783:Endothelial Cells / Q000378:metabolism; D006072:Gossypol / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D011471:Prostatic Neoplasms / Q000503:physiopathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D042442:Vascular Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D042442:Vascular Endothelial Growth Factors; D051020:bcl-X Protein; D040301:Vascular Endothelial Growth Factor Receptor-2; D006072:Gossypol